Antagonism of transforming growth factor-Beta signaling inhibits fibrosis-related genes.

In the fibrotic process, the transforming growth factor-beta1 (TGF-beta1)/Smad3 (Sma- and Mad-related protein 3) signaling plays a central role. To screen for antagonists of TGF-beta1/Smad3 signaling and to investigate their effects on the genes related to fibrosis, we construct a molecular model with a luciferase reporter gene. Results showed that both SB-431542 [4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide] and small interference RNA (siRNA) against Smad3 could dose-dependently suppress the reporter gene. More importantly, they both significantly inhibited the expression of plasminogen activator inhibitor-type 1 (PAI-1) and type I collagenalpha1 (Col Ialpha1) genes in rat hepatic stellate cells. Thus, SB-431542 and Smad3/siRNA may be potential therapeutics for fibrosis.